Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Network mechanisms and dysfunction within an integrated computational model of progression through mitosis in the human cell cycle. PLoS Comput Biol 2020 04;16(4):e1007733

Date

04/07/2020

Pubmed ID

32251461

Pubmed Central ID

PMC7162553

DOI

10.1371/journal.pcbi.1007733

Scopus ID

2-s2.0-85083620688   3 Citations

Abstract

The cellular protein-protein interaction network that governs cellular proliferation (cell cycle) is highly complex. Here, we have developed a novel computational model of human mitotic cell cycle, integrating diverse cellular mechanisms, for the purpose of generating new hypotheses and predicting new experiments designed to help understand complex diseases. The pathogenic state investigated is infection by a human herpesvirus. The model starts at mitotic entry initiated by the activities of Cyclin-dependent kinase 1 (CDK1) and Polo-like kinase 1 (PLK1), transitions through Anaphase-promoting complex (APC/C) bound to Cell division cycle protein 20 (CDC20), and ends upon mitotic exit mediated by APC/C bound to CDC20 homolog 1 (CDH1). It includes syntheses and multiple mechanisms of degradations of the mitotic proteins. Prior to this work, no such comprehensive model of the human mitotic cell cycle existed. The new model is based on a hybrid framework combining Michaelis-Menten and mass action kinetics for the mitotic interacting reactions. It simulates temporal changes in 12 different mitotic proteins and associated protein complexes in multiple states using 15 interacting reactions and 26 ordinary differential equations. We have defined model parameter values using both quantitative and qualitative data and using parameter values from relevant published models, and we have tested the model to reproduce the cardinal features of human mitosis determined experimentally by numerous laboratories. Like cancer, viruses create dysfunction to support infection. By simulating infection of the human herpesvirus, cytomegalovirus, we hypothesize that virus-mediated disruption of APC/C is necessary to establish a unique mitotic collapse with sustained CDK1 activity, consistent with known mechanisms of virus egress. With the rapid discovery of cellular protein-protein interaction networks and regulatory mechanisms, we anticipate that this model will be highly valuable in helping us to understand the network dynamics and identify potential points of therapeutic interventions.

Author List

Terhune SS, Jung Y, Cataldo KM, Dash RK

Authors

Ranjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anaphase-Promoting Complex-Cyclosome
Antigens, CD
CDC2 Protein Kinase
Cadherins
Cdc20 Proteins
Cell Cycle
Cell Cycle Proteins
Computational Biology
Humans
Kinetics
Mitosis
Models, Theoretical
Phosphorylation
Protein Interaction Maps
Proto-Oncogene Proteins